4. Basic mechanisms and potential targets
4.1 Disturbed skin barrier (FLG, pH, microbiome)
The skin barrier in AE is disturbed on multiple levels, including physical, chemical, immunological, neurologic, and microbial components [1].
Martin et al recently summarized genetic risk factors for AE, many of them belonging to extracellular matrix components and its modulators (e.g. FLG, COL5A3, COL6A6, and MMP9, TMEM79) [50, 51]. A variety of AE mice models are used to investigate skin barrier defects, among them FLG ft/ft mice [52], Hrnr-/- mice [53], and TMEM79-/- mice [51]. One major genetic predisposition for the development of AE are loss-of-function mutations in the skin barrier gene filaggrin [54]. Degradation products of histidine-rich filaggrin support the healthy skin barrier as natural moisturizing factors (NMF) and simultaneously maintain an acidic skin pH [55]. The skin pH in AE and especially AE lesions was reported to be increased [56]. In line, an acidic skin pH is associated with low scaling and high hydration, whereas alkaline skin pH is associated with skin barrier dysfunction and decreased stratum corneum integrity [57, 58]. Alkalization of the skin pH directly modulates the activity of the stratum corneum located serine protease kallikrein 5 (KLK5) which has the ability to degrade cell junction proteins, leading to barrier dysfunction and itch [59]. Recently, exogenic mutations in the KLK5 inhibitor Lympho-epithelial Kazal-type-related inhibitor (LEKTI) were associated with AE, supporting the importance of protease activity in the disease [60]. Furthermore, the lipid composition of the skin is abnormal in AE. Changes in ceramides and free fatty acids were reported, the latter correlating with the skin microbiome composition [61, 62].
A skin microbiome dysbiosis towards Staphylococcus aureus and decreased microbial diversity is another hallmark of AE [63]. The intrinsic and extrinsic factors shaping the skin microbiome are complex and yet poorly understood [35]. However, several factors relevant in AE are known to influence the microbiome. The acidic skin pH of healthy skin for example limits the growth of harmful skin bacteria as S. aureus and enhances the growth of the commensal S. epidermidis[64, 65]. Genetics also shape the skin microbiome as recently shown in a mouse model: wild-type and Flgft/ft mice significantly differed in the skin microbiome composition, revealing less diversity with an increased staphylococci colonization [52]. In this study, AE did not develop under germ free conditions but was dependent on microbial colonization and subsequent IL-1beta induction [52]. Both alpha-diversity and S. aureus abundance correlate with disease severity. However, this association seems to depend on the skin site and could be shown for the thigh but not the back of AE patients in a recent study [66]. Not only the presence of S. aureus but also capability of S. aureus strains to produce biofilm and toxins is associated with AE severity [63, 67] [67, 68]. S. aureusactivates the immune system in AE amongst others by the expression of proteases, toxins, superantigens and other virulence factors [63, 69] (Fig. 2). Interestingly, cigarette smoke redirects S. aureus towards virulence factor associated with persisting infection and could therefore explain the avoidable risk factor of tobacco smoke for AE [25, 70]. The virulence factors trigger a vicious cycle in AE. The stimulation of the immune system shapes the inflammatory environment, the expression of IL-31 causes itch and the resulting scratching further damages the skin barrier. The complex interaction between S. aureus and the innate and adaptive immune system has been nicely summarized by Yoshikawa et al 2019 [63].
In the context of itch and scratch-response, sensory neurons are important [71]. However, the nervous system is not only responsible for pruritus, but also modulates the immune response in AE [72].